Scleroderma, or systemic sclerosis (SSc), is an autoimmune connective tissue disorder characterized by inflammation, fibrosis and vasculopathy. Right heart failure caused by pulmonary arterial hypertension (PAH) is the leading cause of death in individuals with SSc, and approximately 10 to 15% of individuals with SSc will develop associated PAH (SSc-PAH). The combination of medical treatment options and systematic, routine screening has improved two-year survival for SSc-PAH, yet current screening tools are inadequate and the condition continues to remain under-diagnosed until it is too late. Preliminary data I have obtained demonstrate that even though resting PA pressures may be normal in SSc-PAH patients, hemodynamic evaluation during bicycle ergometry may unveil occult PAH. In fact, my preliminary data show 12 % of SSc patients with normal resting intra-cardiac pressures developed exercise pulmonary hypertension (mean pulmonary artery pressure e25 mmHg, pulmonary capillary wedge pressure d15 mmHg). In order to understand potential mechanisms which may contribute to the development of PAH, our laboratory has focused on the role of specific cell surface enzymes responsible for the catalytic degradation of purine nucleotides, which my mentor's group has shown to be critical regulators of thrombosis and inflammation at the vessel wall/blood interface. One of these ectoenzymes, CD39, is found on the surface of endothelial cells and leukocytes. In my own published data, I have shown that CD39 can be specifically measured on plasma microparticles obtained from patients with PAH. In fact, these microparticles retain their catalytic activity, and are surprisingly elevaed in patients with PAH compared with controls.6 My preliminary data also indicates that alterations in the concentrations of plasma nucleotides and adenosine (the CD39-mediated metabolites of ATP dephosphorylation) may contribute to pulmonary hypertension. These preliminary data lead me to hypothesize that a combination of early hemodynamic factors, right ventricular strain, and circulating plasma biomarkers can be used to identify patients with sub-clinical SSc-PAH who are at risk for the development of overt SSc-PAH. This proposal will study 225 patients with SSc who are at risk for developing PAH, as well as 75 healthy controls, to determine the extent to which hemodynamic parameters, echocardiographic markers of RV strain, and novel plasma microparticle and nucleotide biomarkers obtained at rest and during exercise can predict the development of SSc-PAH. I will complete this project under the mentorship of physician researchers with domain expertise in vascular biology, pulmonary arterial hypertension, SSc, biomarkers and bioinformatics, all of whom have strong track records of training and peer-reviewed funding. My project and relevant didactic coursework will serve as a training vehicle for me during this career development award by enabling me to learn elements of patient recruitment, data management, statistical analysis, acquisition/interpretation of meaningful hemodynamic and echocardiographic research data, and laboratory based analysis of plasma-based biomarkers of disease progression. This program, including didactic, immersive, and mentored components, will prepare me for an independent research career in patient-oriented research.